The Truth about Interventions In Aseptic Processing

Aseptic processing has advanced over the past several decades, yet the pharmaceutical industry is still accepting of its limitations, particularly as it relates to human intervention as a source of contamination. The authors explain the importance of further diminishing the role of operators in aseptic processing and the approaches and technologies needed to achieve that goal.

Aseptic processing is widely used for preparing sterile products. Although regulatory authorities and industry experts emphasize the sterility-assurance advantages of terminal sterilization, the fact remains that most products being introduced today must be manufactured aseptically (1). Implicit in aseptic processing is the notion that items are first sterilized and then processed under aseptic conditions into the final product. More often than not, that assembly involves the labor of one or more appropriately gowned individuals in a pristine environment. The operators' typical activities will include the set-up, filling or assembly process, and environment monitoring of the processing area.

The evolution of aseptic processing

During the past 50 years, aseptic processing has evolved. Before the advent of the high-efficiency particulate air (HEPA) filter and cleanroom, aseptic processing was performed by operators working in gloveboxes that separated them from the sterilized materials. This approach afforded a degree of isolation between the operator and the sterilized items they were charged with handling and assembling, which helped ensure the sterility (or perhaps more accurately the safety) of the final product.

In the mid-1950s, HEPA filters became available to industry and were quickly adopted to provide large areas in which equipment could perform the majority of the aseptic processing activities. The operators, now garbed in sterilized garments, were still present to initially set up the equipment, perform any needed equipment adjustments, address component malfunctions, and collect environmental samples. Over the years, many improvements to cleanroom operations occurred. Equipment reliability improved, and air changes were increased. Sterilization processes were validated, and gowning materials became more comfortable and robust. And barriers were introduced.

Restricted access barrier systems. The most evolved cleanroom-based designs today are restricted access barrier systems (RABS) in which operator access to the aseptic environment is severely limited (2). RABS and all of the prior technological advances in aseptic processing were implemented because there was a clear understanding that personnel were the only significant source of microbial contamination in conventional cleanroom aseptic processing.

Isolators. Some 20 years ago, before the advent of RABS technology, the original gloveboxes of aseptic processing antiquity were reincarnated as isolators. Isolators were a substantial improvement over gloveboxes. The isolators were supplied with HEPA-filtered air that enabled these enclosures to be maintained at a positive pressure relative to the surrounding environment, mitigating issues with leaks and with finished-product out-feed isolators. The isolators could be reproducibly decontaminated and could be connected to other isolators and process equipment in a way that maintained separation between the internal environment and operating personnel (3, 4). These advancements were a technological breakthrough of substantial magnitude, and some two decades after their introduction, isolators continue to represent the pinnacle of aseptic processing technology.

Aseptic processing today

Although that might be the end of an interesting story, present-day operations use all of these aseptic technologies, and new cleanrooms for aseptic processing still are in the planning stages. All present-day aseptic processing systems require to some extent the direct participation of operators with sterilized materials just as they always have. Using the word sterilized rather than sterile is not a compliance hedge. It is the recognition that once any material is placed in a manned cleanroom and handled by personnel, it legitimately cannot be considered sterile no matter how much overkill was applied in its validation. Cleanroom operators use utensils in their gloved hands, and RABS and isolator operators use the equipment's gloves in much the same manner. There are truly refined aseptic processing concepts available that perform without operators. As with any new technology in the extremely conservative pharmaceutical industry, however, the implementation of these concepts, although certainly desirable, is by no means imminent and is unlikely to be universal for many years. (It should be noted that high levels of automation already are widely used in other clean and aseptic industries). Although we hope that in two decades aseptic processing in the pharmaceutical industry will have taken advantage of the numerous technological advancements that are available even today, their adoption is by no means a sure thing.